In the US duodenal ulcer remains a common disease associated with substantial morbidity, mortality, and economic cost of greater than $3 billion/yr. Studies of the pathophysiology of duodenal ulcer have been directed at the "aggressive" factors, while the "defensive" factors that protect the human duodenum from acid-peptic damage have not been thoroughly examined and HCO3-secretion by the human duodenum not at all. Recent in vitro and in vivo animal studies indicate that: the duodenal surface epithelial cells secrete HC03-at rest and secretion significantly increases in response to agonists (e.g. H+, prostaglandin E2, and some GI hormones); cyclooxygenase and carbonic anhydrase inhibitors suppress duodenal HC03-secretion; there is a gradient for duodenal HCO3- secretion (proximal greater than distal); and in animals transport involves both electroneutral (Cl-/HC03-exchange) and electrogenic mechanisms. The aims of this proposal are to: 1) Systematically examine in vivo duodenal mucosal bicarbonate secretion in segments free of biliary and pancreatic bicarbonate - factors that regulate duodenal HC03-secretion and their relative potencies and efficacies will be determined, 2) Quantitate duodenal HC03-secretion in normal subjects and patients with duodenal ulcer (active and inactive) and duodenitis, 3) Contrast HC03-secretion in proximal and distal duodenal segments to determine if a duodenal gradient exists, and 4) Determine the mechanisms that regulate duodenal HC03-secretion in man. Preliminary in vivo studies in man indicate: 1) The human proximal duodenum can be isolated free of pancreaticobiliary secretion and basal proximal duodenal HC03 secretion is approximately 175 umo1/cmcm-h, 2) Intraluminal H+ significantly increases bicarbonate secretion, and 3) Substantiation of C1- with S04= significantly decreased bicarbonate secretion indicating the presence of C1-HC03-exchange mechanism. These experiments will provide important information regarding the physiology and pathophysiolgy of duodenal HC03- secretion in health and patients with acid-peptic diseases of the duodenum. These results will likely have an impact on prevention and treatment of duodenal ulcer and related diseases.